Thorup CV; Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 69, 8200, Aarhus N, Denmark.
Jeppesen CNA; Jensen TH; Tinggaard AB; Rudd CL;Hvas CL; Skou MK; Mortensen JK;Reggiori F; Dengjel J; Wang J; Farup J; Jessen N; Kim WY; Wiggers H;

Trials [Trials] 2025 Oct 30; Vol. 26 (1), pp. 452.
Date of Electronic Publication: 2025 Oct 30.

Background: Coronary artery disease (CAD) remains a major cause of morbidity and mortality. Caloric restriction promotes cardiovascular health but is difficult to sustain. Spermidine, a naturally occurring polyamine and caloric-restriction mimetic, has been linked to improved longevity in epidemiological studies and shown to enhance autophagy, mitochondrial function, and cardiovascular ageing in preclinical models. This trial will investigate whether high-dose spermidine improves cardiac remodelling, exercise capacity, muscle mass, and systemic inflammation in elderly patients with CAD.
Methods: This is a single-centre, randomised, double-blind, placebo-controlled, superiority trial at Aarhus University Hospital, Denmark. We have randomised 187 patients aged ≥ 65 years with CAD (prior coronary artery revascularisation or myocardial infarction ≥ 3 months prior to screening) and preserved left ventricular ejection fraction (> 40%) in a 1:1 ratio to receive either 24 mg/day spermidine or placebo for 48 weeks. Participants, investigators, outcome assessors, and data analysts will remain blinded until completion of the analysis of all primary endpoints. Analyses will follow the intention-to-treat principle. The trial is powered to detect between-group differences in four co-primary endpoints: (1) left ventricular mass (g) by cardiac magnetic resonance imaging, (2) peak oxygen consumption (mL·kg⁻ ¹ ·min⁻ ¹ ) by cardiopulmonary exercise testing, (3) appendicular lean mass (g) by dual-energy X-ray absorptiometry, and (4) high-sensitivity C-reactive protein (mg/L). Secondary outcomes include 24-h ambulatory blood pressure, arterial stiffness, physical performance, muscle strength, daily physical activity, quality of life, cognitive function, dietary spermidine intake, and spermidine levels in plasma and skeletal muscle. Safety monitoring includes laboratory testing, telephone interviews and adverse event recording.
Discussion: This is the first trial to investigate the cardiovascular and metabolic benefit from a high-dose spermidine treatment in patients with CAD. The findings will provide important insights into the therapeutic potential of spermidine.
Trial Registration: ClinicalTrials.gov identifier NCT06186102 (first posted 12 June 2023). Participant enrolment began on 4 January 2024, and trial completion is anticipated in August 2026.
Competing Interests: Declarations. Ethics approval and consent to participate {24}: The study will follow the tenets of the Declaration of Helsinki, and the protocol was approved by the Danish ethics committees. Informed consent will be obtained from all the participants. Consent for publication {32}: Not applicable: this protocol does not include any individual person’s data (images, videos, or personal details). Competing interests {28}: The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this work. Henrik Wiggers reports receiving research grants from Sygesikring Danmark and the Eva and Frænkels Mindefond. Christian Velling Thorup reports receiving research grants from the Danish Diabetes and Endocrine Academy and the Danish Cardiovascular Academy (grant numbers NNF22SA0079901 and NNF20SA0067242), as well as funding from the Steno Diabetes Center Aarhus (SDCA). The spermidine intervention and placebo capsules were donated by DoNotAge (4 Melbourne Business Ct, Derby, Derbyshire, DE24 8LZ, UK). The investigators have no financial or advisory relationship with the company, and the donor had no role in the design, conduct, analysis, or reporting of the trial.